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Responsabile: prof. Paolo Gasparini
Background and Significance
Most common diseases have are due to a combination of genetic and environmental risk factors. Genome Wide Association Studies (GWAS) discovered many genetic loci influencing such traits and diseases. In most cases however they explain a small percentage of trait heritability and cannot yet provide precise risk prediction nor predict the response to therapies. Several explanations for this missing heritability have been proposed. Current GWAS have interrogated a limited number of variants with frequencies of at least 5%¿10%. A role for additional common variants of small effect and less common to private variants was suggested as well as non additive interactions and epigenetic effects. Lack of sufficient information on genome variation was recently overcome by advances in sequencing technologies, that enable to assess all individual variation and particularly rare and private ones. Genetically isolated populations proven useful in the study of Mendelian and complex traits, are expected to provide new opportunities for identifying rare variants. Because the entire population can be studied, the relative weight of environmental variation can be controlled and genetic factors can be more easily identified due to their origin form a small number of ancestors and isolation, they may represent a valid support to a detailed description of the genetic variability responsible for complex disorders such as cardiovascular disorders, that affect a large proportion of the population.
Specific aims
Aim 1: The Italian Network of Genetic Isolates (INGI) includes a series of isolated populations that, being spread across the country, may quite well represent the Italian general population. The first aim will be the definition, using Whole Genome Sequencing (WGS). of most of the genetic variation of the INGI isolates including novel variants not yet described in large sequencing projects like 1000G.
Aim 2: Data from Aim1 will be used to construct a framework for a detailed characterization of the genetic variability of the general population in Italy particularly in respect to risk for cardiovascular disorders. Association analysis for traits such as anthropometric measures, serum lipid levels, blood pressure, hematological parameters and others, available for all the INGI populations and known risk factors for cardiovascular disorders will be done. We expect to identify variants characteristics of the Italian population in known as well in novel loci that may be enriched in isolated populations.
Aim 3: Analysis of the populations structure and substructure with a given focus on purifying selection (GERP score), inbreeding depression and purging to better understand the role of rare variants, and the presence/effect of selection (i.e. environment).
Hypothesis
The applicants and the Italian researcher abroad have a large experience in the study of complex disorders and contributed to many large metanalysis for complex traits over the last years. The INGI populations originate from geographically isolated regions in North West, North West and Southern Italy. The basic idea is to combine the powerful tool of NGS technologies with the availability of more than 400 phenotype endpoints including, many of the well known risk factors for cardiovascular disorders, anthropometric measures, blood pressure, alcohol intake, lifestyle habits, disease status (self-reported), drug intake, blood count and clinical biochemistry, ECG, echo, nutrition questionnaires, food preferences and many others to identify a list of rare variants underlying cardiovascular diseases.
Preliminary data
A total number of >5000 DNAs have been genotyped (Illumina 370k or OMNI arrays). Genetic analyses have demonstrated high levels of genetic isolation, with >80% endogamy, drift from other European populations, and the presence of a relatively large inbreeding confirming that INGI populations are bon fide genetic isolates and could contribute to the identification of novel variants with large effect as suggested. As regards WGS, 384 unrelated individuals well representing the differences within each cohort were already sequenced at an average 6x depth and the analysis is in progress. Preliminary data indicate that more than 1 million novel variants (including rare ones) were already identified for one of the cohort confirming the feasibility and usefulness of our approach.
Materials and Methods
WGS will be carried out using internal and external facilities. After QC and bioinformatics analysis of the data, variants will be imputed into the remaining genotyped populations using IMPUTE2 or similar algorithms. Because of the population structure and the availability of large genealogies, long shared haplotypes can be identified which will allow very high accuracy imputation for genotyped samples. Variants will be analyzed in each cohort for association with quantitative and qualitative traits of interest (i.e cardiovascular traits), using different statistical tests including some more appropriate for genetic isolates. Comparisons within the different INGI cohorts as well as with other populations will be carried out. In particular, the UK10k population studied by Dr. Soranzo and other genetic isolates from Europe and eventually cohorts from the general population in Italy will be used.
Impact and Translational Implications
GWAS have highlighted the potential for genomic information to transform health care by largely enabling genetic tests to refine risk prediction and to predict the response to therapies. At the end of the project we expect to have defined a large set of variations in Italy that could be quickly translated into molecular tests including pharmacogenetics ones. Resultscould also provide information on mechanism of disease and hints into new and personalized therapeutic intervention.
